We optimize DNA vaccine procedures for AIDS and eventually other applications. We used optimization of antigen form, expression and delivery to achieve optimal results. The optimized DNA vectors were shown to provide protection from high viremia in both prophylactic and therapeutic vaccination of rhesus macaques infected by SIV, the most faithful primate model for AIDS. We have used molecular adjuvants to increase immune response to DNA vaccination in collaborative studies. We have shown that IL-12 increased both humoral and cellular immune response to SIV DNA vectors in macaques. We have also shown that the optimized DNA is excellent in priming immune response in DNA prime-virus vector boost. The HIV optimized vectors are in clinical trials. The development of several vector combinations from our lab provides the opportunity for additional clinical applications in AIDS and cancer.